A large number of cytokines participate in the inflammatory response, including IL-1, IL-6, IL-8 and TNF-α. Overproduction of cytokines such as IL-1 and TNF-α are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others (Henry et al., Drugs Fut., 24:1345–1354 (1999); Salituro et al., Curr. Med. Chem., 6:807–823 (1999)). Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, monoclonal antibody to TNF-α (Enbrel) (Rankin et al., Br. J. Rheumatol., 34:334–342 (1995)), and soluble TNF-α receptor-Fc fusion protein (Etanercept) (Moreland et al., Ann. Intern. Med., 130:478–486 (1999)).
The biosynthesis of TNF-α occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-α production are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. These kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes.
There are four known isoforms of p38, i.e., p38-α, p38β, p38γ, and p38δ. The α and β isoforms are expressed in inflammatory cells and are key mediators of TNF-α production. Inhibiting the p38α and β enzymes in cells results in reduced levels of TNF-αexpression. Also, administering p38α and β inhibitors in animal models of inflammatory disease has proven that such inhibitors are effective in treating those diseases. Accordingly, the p38 enzymes serve an important role in inflammatory processes mediated by IL-1 and TNF-α. Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-α for use in treating inflammatory diseases are disclosed in U.S. Pat. Nos. 6,277,989 and 6,130,235 to Scios, Inc; U.S. Pat. Nos. 6,147,080 and 5,945,418 to Vertex Pharmaceuticals Inc; U.S. Pat. Nos. 6,251,914, 5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Pat. Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01/27089 to Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors).
U.S. application Ser. No. 10/420,399 filed Apr. 22, 2003 (hereinafter the Ser. No. 10/420,399 application) discloses compounds which are inhibitors of p38 kinase, which may be used for treating p38 kinase associated conditions including rheumatoid arthritis, and which compounds have the formula (I)
enantiomers, diastereomers, salts, and solvates thereof, wherein    X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO2—, —C(═O)—, —CO2—, —NR8—, —NR8C(═O)—, —NR8C(═O)NR9—, —NR8CO2—, —NR8SO2—, —NR8SO2NR9—, —SO2NR8—, —C(═O)NR8—, halogen, nitro, and cyano, or X is absent;    Z is —C(═O)NR10—Bb, —(CH2)—C(═O)NR10—Bc, —NR10a C(═O)—Ba, —(CH2)—NR10aC(═O)—Bc, —NR10aC(═O)NR10—B, —NR10SO2—B, —SO2NR10—B, —C(═O)Ba, —CO2—Be, —OC(═O)—Ba, —C(═O)NR10—NR10a—Bd—NR10CO2—Ba or —C(═O)NR10—(CH2)C(═O)Ba;    B is            (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl; or        (b) aryl substituted with one R11 and zero to two R12;            Ba is optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl;    Bb is            (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl;        (b) aryl substituted with one R11 and zero to two R12; or        (c) —C(═O)R13, —CO2R13, —C(═O)NR13R13a;            Bc is optionally substituted alkyl, optionally substituted alkoxy, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl;    Bd is hydrogen, —C(═O)R13, or —CO2R13;    Be is hydrogen, optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl;    R1 and R5 are independently selected from hydrogen, alkyl, substituted alkyl, —OR14, —SR14, —OC(═O)R14, —CO2R14, —C(═O)NR14R14a, —NR14R14a, —S(═O)R14, —SO2R14, —SO2NR14R14a, —NR14SO2NR14aR14b, —NR14aSO2R14, —NR14C(═O)R14a, —NR14CO2R14a, —NR14C(═O)NR14aR14b, halogen, nitro, and cyano;    R2 is hydrogen or C1-4alkyl;    R3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, NH2, or NH(CH3);    R4 is selected from:            (a) hydrogen, provided that R4 is not hydrogen if X is —S(═O)—, —SO2—, —NR8CO2—, or —NR8SO2—;        (b) alkyl, alkenyl, and alkynyl optionally independently substituted with keto and/or one to four R17;        (c) aryl and heteroaryl either of which may be optionally independently substituted with one to three R16; and        (d) heterocyclo and cycloalkyl either of which may be optionally independently substituted with keto and/or one to three R16; or        (e) R4 is absent if X is halogen, nitro, or cyano;            R6 is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each R6 group in turn may be further substituted by one to two R18;    R8 and R9 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl;    R10 and R10a are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, and aryl;    R11 is selected from            (a) alkyl, haloalkyl, alkoxy, haloalkoxy, —SO2alkyl, cycloalkyl, heterocyclo, and heteroaryl any of which may be optionally substituted; or        (b) halo, cyano, amino, alkylamino, and dialkylamino;            R12 is selected from alkyl, R17, and C1-4alkyl substituted with keto (═O) and/or one to three R17;    R13 and R13a are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted aryl;    R14, R14a and R14b are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, except when R14 is joined to a sulphonyl group as in —S(═O)R14, —SO2R14, and —NR14aSO2R14, then R14 is not hydrogen;    R16 is selected from alkyl, R17, and C1-4alkyl substituted with keto (═O) and/or one to three R17;    R17 is selected from            (a) halogen, haloalkyl, haloalkoxy, nitro, cyano, —SR23, —OR23, —NR23R24, —NR23SO2R25, —SO2R25, —SO2NR23R24, —CO2R23, —C(═O)R23, —C(═O)NR23R24, —OC(═O)R23, —OC(═O)NR23R24, —NR23C(═O)R24, —NR23CO2R24;        (b) aryl or heteroaryl either of which may be optionally substituted with one to three R26; or        (c) cycloalkyl or heterocyclo optionally substituted with keto(═O) and/or one to three R26;            R18 and R26 are independently selected from C1-6alkyl, C2-6alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C1-4alkylamino, aminoC1-4alkyl, hydroxy, hydroxyC1-4alkyl, alkoxy, C1-4alkylthio, aryl, heterocyclo, (aryl)alkyl, aryloxy, and (aryl)alkoxy;    R23 and R24 are each independently selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo;    R25 is selected from alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl and heterocyclo; and    m is 0, 1, 2 or 3.
The 10/420,399 application further discloses that the compounds of formula (I) may be prepared using the following reaction sequences.

Scheme 1 is described as follows.
“Commercially-available compound (1) can be reacted with oxalyl chloride with heating and then concentrated in vacuo and reacted with an amine B—NH2 in the presence of a base, such as diisopropylamine, in an organic solvent, such as DCM to yield compound (2). Compound (2) can be reacted with hydrogen in the presence of a catalyst, such as Pd, in an alcoholic solvent, such as EtOH, at rt to afford compound (3). Compound (3) can then be used as in Scheme 2 to produce compounds (8) of Scheme 2.”

Referring to Scheme 2, 3-methyl-1-pyrrole-2,4-diethyl ester can be reacted with chloramine in ether to produce compound (4). Reacting compound (4) in formamide with acetic acid produces compound (5). Compound (5) can be reacted with DIPEA and POCl3 in toluene to produce compound (6). Compound (6) can be reacted with DIPEA and compound (3) in DMF to produce compound (7). Compound (7) is hydrolyzed in THF with NaOH to produce acid intermediate (7a) which upon treatment with HOBt, EDCI and the appropriate amine (7b) in DMF produces compound (8).
Included among the many compounds covered by the Ser. No. 10/420,399 application is the compound of the structure
also referred to as 4-[[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide or the free base thereof.
As can be seen from the above Reaction Scheme 2, the ester 7 is converted to the amide 8 employing a two step process wherein ester 7 is hydrolyzed to the corresponding acid 7a which is made to undergo a coupling reaction with the amine 7b to produce the amide 8.
Although the above two step procedure for producing amide 8 from ester 7 is adequate, any improvement in such two step procedure which involved direct conversion of ester 7 to amide 8 (without the hydrolysis step) would be a most welcome improvement.